Amplification and high levels of expression of the EGF receptor are known to play an essential role in the pathogenesis of glial tumors, where the gene is frequently rearranged. We have identified a novel variant of the EGF receptor, called mLEEK, which results from a large in-frame deletion. mLEEK has been detected in glial tumors as well as other tumor types, but not in normal brain. The functional domains conserved suggest that mLEEK plays a role in signal transduction and thus represents a key new element in the EGF receptor signaling network. Moreover, the unique junction in mLEEK creates a novel epitope and raises diagnostic and therapeutic possibilities similar to those already in clinical practice for other EGFR variants. The goals of this proposal are to characterize mLEEK expression patterns and molecular function as well as to investigate its role in cell signaling and pathogenesis of brain tumors. A broad range of glial tumor specimens will be screened for mLEEK expression. Cell culture systems will be implemented to study the role of mLEEK in cell signaling and the transforming and tumorigenic properties of mLEEK will be examined using a variety of approaches. These studies will lay the framework for future translational research efforts.